Variant 19-40013677-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_178544.5(ZNF546):c.407A>G(p.Lys136Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000405 in 1,504,450 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000014 ( 0 hom., cov: 28)

Exomes 𝑓: 0.000043 ( 0 hom. )

Consequence

ZNF546
NM_178544.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.123

Variant links:

Genes affected

ZNF546 (HGNC:28671): (zinc finger protein 546) Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Predicted to be integral component of membrane. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ZNF546 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.055714756).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF546	NM_178544.5 linkuse as main transcript	c.407A>G	p.Lys136Arg	missense_variant	7/7	ENST00000347077.9	NP_848639.2	Q86UE3B3KVL3
ZNF546	NM_001297763.2 linkuse as main transcript	c.329A>G	p.Lys110Arg	missense_variant	7/7		NP_001284692.1	Q86UE3M0QY24B3KVL3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF546	ENST00000347077.9 linkuse as main transcript	c.407A>G	p.Lys136Arg	missense_variant	7/7	1	NM_178544.5	ENSP00000339823.3		Q86UE3

Frequencies

GnomAD3 genomes

AF:

0.0000135

AC:

AN:

147948

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000297

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000106

AC:

AN:

188864

Hom.:

AF XY:

0.00000966

AC XY:

AN XY:

103516

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000111

Gnomad OTH exome

AF:

0.000230

GnomAD4 exome

AF:

0.0000435

AC:

AN:

1356502

Hom.:

Cov.:

AF XY:

0.0000314

AC XY:

AN XY:

668938

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000529

Gnomad4 OTH exome

AF:

0.0000540

GnomAD4 genome

AF:

0.0000135

AC:

AN:

147948

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

72016

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000297

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000346

Hom.:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 29, 2023

The c.407A>G (p.K136R) alteration is located in exon 7 (coding exon 5) of the ZNF546 gene. This alteration results from a A to G substitution at nucleotide position 407, causing the lysine (K) at amino acid position 136 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.71

CADD

Benign

5.2

DANN

Benign

0.91

DEOGEN2

Benign

0.0026

.;.;T

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.070

M_CAP

Benign

0.0026

MetaRNN

Benign

0.056

T;T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.20

.;.;N

PrimateAI

Benign

0.34

PROVEAN

Benign

-0.36

.;.;N

REVEL

Benign

0.065

Sift

Benign

0.56

.;.;T

Sift4G

Benign

1.0

T;T;T

Polyphen

0.12

.;.;B

Vest4

0.068, 0.064

MutPred

0.42

.;.;Loss of ubiquitination at K136 (P = 0.0087);

MVP

0.48

MPC

0.14

ClinPred

0.033

GERP RS

2.5

Varity_R

0.025

gMVP

0.015

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.13

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over